Objectives: To evaluate the efficacy of nizatidine, a histamine H2-blocking drug, in delaying the progression of cognitive impairment in older adults with Alzheimer disease (AD). Design: A one-year, randomized, double-blind, placebo-controlled trial. Participants: Fifty-one older men and women aged 67 to 96 years with AD were recruited from the Cache County Study on Memory in Aging. Methods: Patients were stratified by age and by the presence of one or more ε4 alleles at the APOE locus, then randomized to receive nizatidine 75 mg (Axid AR™, Whitehall Robins) or a matching placebo tablet twice daily. Cognitive outcomes were assessed at baseline, six, and twelve months after enrollment using tests from the CERAD battery and additional measures of visuospatial memory, verbal memory, and verbal fluency. Results: Subjects showed significant declines in language, fluency, and praxis but most measures of memory had already bottomed out. Intention-to-treat and compliance-based analyses showed no effect of nizatidine on any of the cognitive outcome measures over the one-year study interval. Conclusions: These results do not support claims for the efficacy of nizatidine in over-the-counter dosages as a means of preventing symptom progression in AD.